This invention describes various processes for synthesis and resolution of racemic amino-substituted fused bicyclic ring systems, in particular, amino-substituted tetrahydroquinolines or tetrahydroisoquinolines. One process utilizes selective hydrogenation of an amino-substituted fused bicyclic ring. An alternative process prepares a racemic amino-substituted fused bicyclic ring system via nitrosation. In addition, the present invention describes the enzymatic resolution of a racemic mixture to produce the (R)- and (S)-forms of amino-substituted fused bicyclic ring systems, such as amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline. Another aspect of the invention describes a process to racemize the enantiomerically enriched (R)- and (S)-forms of amino-substituted fused bicyclic ring systems. Further provided by this invention is an asymmetric synthesis of an amino-substituted fused bicyclic ring to produce the desired enantiomer.
It is desired by those of skill in the art to produce enantiomeric forms of pharmaceutical compounds, since such enantiomers often have increased activity for selected diseases when compared with the racemic form of the same compound. For example, 8-amino-5,6,7,8-tetrahydroquinolines are utilized as intermediates in the preparation of novel heterocyclic compounds that bind to chemokine receptors and demonstrate protective effects against infection of target cells by human immunodeficiency virus (HIV). See WO 00/56729.
Approximately 40 human chemokines have been described, that function, at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs, 7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute a family of proteins, approximately 8-10 kDa in size. Chemokines appear to share a common structural motif, that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the xe2x80x9cCCxe2x80x9d or xcex2-chemokines and the xe2x80x9cCXCxe2x80x9d or xcex1-chemokines. The receptors of these chemokines are classified based upon the chemokine that constitutes the receptor""s natural ligand. Receptors of the xcex2-chemokines are designated, xe2x80x9cCCRxe2x80x9d; while those of the xcex1-chemokines are designated xe2x80x9cCXCRxe2x80x9d.
Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation. More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta et al., J. Biolog. Chem., 7:4282-4287, 1998). Two specific chemokines have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
For example, U.S. Pat. Nos. 5,583,131, 5,698,546 and 5,817,807 disclose cyclic compounds that are active against HIV-1 and HIV-2. These compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilizes the CXCR-4 receptor for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural CXC-chemokine for CXCR-4, stromal cell-derived factor 1 xcex1 (SDF-1).
Additionally cyclic polyamine antiviral agents described in the above-mentioned patents have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. See U.S. Pat. No. 6,365,583. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
Therefore, a skilled artisan would be interested in more effective and efficient processes for producing racemates and enantiomers of various ring systems. This invention provides such processes.
The invention provides a process for synthesizing a racemic amino-substituted 5,6,7,8-tetrahydroquinoline or a racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline comprising:
a) reacting an amino-substituted quinoline of the formula I or an amino-substituted isoquinoline of the formula II with an amine-protecting group compound in an organic solvent to produce an amine-protected, substituted quinoline or isoquinoline: 
b) hydrogenating the amine-protected, substituted quinoline or isoquinoline in a strongly acidic solvent at an elevated temperature to form the 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline; and
c) hydrolyzing the amine-protecting group to produce the desired racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline;
wherein NH2 is located at any position on the benzene portion of the quinoline or isoquinoline, R1 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and wherein R1 is selected from the group consisting of nitro, cyano, carboxylic acid, alkyl, alkoxy, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.
The invention also provides a process for synthesizing a racemic amino-substituted 5,6,7,8-tetrahydroquinoline or a racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline comprising:
a) reacting either a substituted 5,6,7,8-tetrahydroquinoline of the formula III or a substituted 5,6,7,8-tetrahydroisoquinoline of the formula IV 
with at least 2 equivalents of an alkyllithium base, or a lithium, sodium, or potassium amide base, and then with a nitrosating agent to form an oxime; and
b) reducing the oxime to produce the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline;
wherein the amino is located at the 8-position on the quinoline or the 5-position on the isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and wherein R2 is selected from the group consisting of halo, nitro, cyano, a protected carboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.
Further provided is a process for synthesizing a keto-substituted 5,6,7,8-tetrahydroquinoline or a keto-substituted 5,6,7,8-tetrahydroisoquinoline comprising:
a) reacting either a substituted 5,6,7,8 tetrahydroquinoline of the formula III or a substituted 5,6,7,8-tetrahydroisoquinoline of the formula IV 
with at least 2 equivalents of an alkyllithium base, or a lithium, sodium, or potassium amide base; and then with a nitrosating agent to form an oxime; and
b) hydrolyzing the oxime to produce the corresponding ketone;
wherein the keto is located at the 8-position on the quinoline or the 5-position on the isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline; m is 0-4; and R2 is selected from the group consisting of halo, nitro, cyano, a protected carboxylic acid, alkyl, alkenyl, cycloalkyl, a protected hydroxyl, a protected thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group, and a heterocyclic group.
Also, this invention provides a process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline of the formula V or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VI to produce the two enantiomers, 
comprising:
a) enantioselectively acylating or carbamoylating the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline using an enantioselective enzyme as a catalyst; and
b) separating the unreacted amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline as the first enantiomer, from the enantiomeric amide- or carbamate-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline; and
c) cleaving the amide or carbamate group to isolate the second enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
wherein NH2 is located at any position on the saturated portion of the quinoline or isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.
Another process is provided for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline of the formula V or amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VI to produce one of the enantiomers, 
comprising:
a) enantioselectively acylating or carbamoylating the racemic amino-substituted 5,6,7,8-tetrahydroquinoline or the racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding unreacted amine in the first enantiomeric form and the reacted amide or carbamate in the second enantiomeric form; and
b) isolating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
wherein NH2 is located at any position on the saturated portion of the quinoline or isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; and R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group.
A process is provided for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline to produce the two enantiomers, comprising:
a) reacting racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII 
with water, an alcohol, or a primary or secondary amine using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding amine in the first enantiomeric form, and the unreacted amide or carbamate in the second enantiomeric form;
b) separating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-tetrahydroisoquinoline, from the unreacted amide or carbamate; and
c) cleaving the amide or carbamate group to produce the second enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-isoquinoline;
wherein the amide or carbamate group is located at any position on the saturated portion of the quinoline or isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group; and R3 is an optionally substituted carbon atom or an optionally substituted oxygen atom.
Additionally, this invention provides a process for resolving racemic amino-substituted 5,6,7,8-tetrahydroquinoline or racemic amino-substituted 5,6,7,8-tetrahydroisoquinoline to produce one of the enantiomers, comprising:
a) reacting racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroquinoline of the formula VII or racemic amide-or carbamate-substituted 5,6,7,8-tetrahydroisoquinoline of the formula VIII 
with water, an alcohol, or a primary or secondary amine using an enantioselective enzyme as a catalyst to produce a mixture of the corresponding amine in the first enantiomeric form, and the unreacted amide or carbamate in the second enantiomeric form; and
b) isolating the first enantiomer of the amino-substituted 5,6,7,8-tetrahydroquinoline or 5,6,7,8-tetrahydroisoquinoline;
wherein the amide or carbamate is located at any position on the saturated portion of the quinoline or isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4; R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group; and R3 is an optionally substituted carbon atom or an optionally substituted oxygen atom.
A process is provided for racemizing an enantiomerically enriched amino-substituted 5,6,7,8-tetrahydroquinoline of the formula XIII or amino-substituted 5,6,7,8-tetrahydroisoquinoline of the formula XIV to produce the corresponding racemic mixture: 
comprising:
a) heating the enantiomerically enriched amino-substituted 5,6,7,8-tetrahydroquinoline or amino-substituted 5,6,7,8-tetrahydroisoquinoline neat or in an organic solvent in the presence or absence of an additive; and
b) when either R7 or R8 is not hydrogen, cleaving the R7 or R8 group under conditions to form the corresponding amino;
wherein NR7R8 is located at any position on the saturated portion of the quinoline or isoquinoline; R2 is located at any other hydrogen position on the quinoline or isoquinoline ring; m is 0-4;
R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thio, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group, and a heterocyclic group; and
R7 and R8 are each selected from the group consisting of hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, aralkyl, alkanoyl, alkylsulfonyl, a carbonyl- or sulfonyl-group substituted by an aromatic or heterocyclic ring, aryloxycarbonyl, alkoxycarbonyl, arylcarbamoyl, alkylcarbamoyl, arylthiocarbonyl, alkylthiocarbonyl, and carbamoyl.
A process is provided for synthesizing an enantiomer of a primary amino-substituted fused bicyclic ring of formula IX comprising: 
a) forming the Schiff base of a keto group located on ring B of the fused bicyclic ring by reacting it with an enantiomerically-pure primary amine chiral auxiliary R*NH2 of the formula X 
xe2x80x83to produce the corresponding enantiomerically-pure imine of the fused bicyclic ring;
b) diastereoselectively reducing the imine to produce the corresponding enantiomerically-pure secondary amine on the fused bicyclic ring; and
c) removing the chiral auxiliary R* to form the enantiomer of the primary amino-substituted fused bicyclic ring;
wherein ring A is a heteroaromatic 5- or 6-membered ring, P is a nitrogen atom, sulfur atom or oxygen atom; ring B is a 5- or 6-membered cycloalkyl or heterocycloalkyl;
wherein NH2 is located at a position on ring B; and R2 is located at any other hydrogen position on the fused bicyclic ring;
wherein m is 0-4; R2 is selected from the group consisting of halo, nitro, cyano, carboxylic acid, alkyl, alkenyl, cycloalkyl, hydroxyl, thiol, a protected amino, acyl, carboxylate, carboxamide, sulfonamide, an aromatic group and a heterocyclic group; and
R4, R5, and R6 are each different and selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, and a 5- or 6-membered aromatic ring; and at least one of R4, R5, or R6 is a 5- or 6-membered aromatic ring.